1. Field of the Invention
The present invention relates to a novel optically active quarternary ammonium salt having C2-symmetric axial chirality, a method for producing thereof, and an intermediate for producing the salt and a method for producing the intermediate. Further, the present invention relates to a method for producing optically active xcex1-amino acid derivatives by stereoselective alkylation using the salts as a phase-transfer catalyst.
2. Description of the Related Art
A method is reported that cincona alkaloid derivatives are used as a phase-transfer catalyst for producing optically active xcex1-amino acid derivatives expressed by a general formula (XXI): 
wherein
R5 is an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an allyl or substituted allyl group having 3 to 9 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; or a propargyl or substituted propargyl group which having 3 to 9 carbon atoms which may be branched; and
* is a newly produced chiral center (Corey, E. J. et al. J. Am. Chem. Soc., 1997, 119, 12414).
The above-mentioned compound of general formula (XXI) are produced by stereoselectively alkylating a glycine derivative expressed by a general formula (XIX): 
in the two phase system comprised of organic solvent and water, with a compound of general formula (XX):
R5xe2x80x94Wxe2x80x83xe2x80x83(XX)
wherein R5 is an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an allyl or substituted allyl group having 3 to 9 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; or a propargyl or substituted propargyl group which having 3 to 9 carbon atoms which may be branched; and W is a functional group having leaving ability.
However, in the above-mentioned conventional method, halogenized solvent should be used as a solvent and since reaction temperature should be very low for producing the chiral derivatives with high purity above-mentioned method is not used for industrial production.
Furthermore, since the phase-transfer catalyst is prepared from cincona alkaloid, it is difficult to modify or prepare derivatives of a catalyst having an excellent stereoselectivity based on the above-mentioned phase-transfer catalyst.
On the other hand, it is not known that optically active quarternary ammonium salt with axial chirality is prepared and used for stereoselective alkylation as a phase-transfer catalyst.
The purpose of the present invention is to provide an optically active quarternary ammonium salt with axial chirality, particularly their spiro derivatives, as a phase-transfer catalyst. The quarternary ammonium salt of the present invention converts glycine derivatives into optically active xcex1-amino acid derivatives by stereoselectively alkylating the glycine derivatives. Moreover, the purpose of the present invention is to provide an intermediates useful for production of the novel quarternary ammonium salt.
The present invention provides a compound of general formula (I): 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and
R1 and R2 may be the same or different;
Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and
Ar1 and Ar2 may be the same or different;
Xxe2x88x92 is a halide anion; and
Y and Z are groups independently selected from the group consisting of a hydrogen atom; a halogen atom; an alkyl group having 1 to 4 carbon atoms; and an alkoxy group having 1 to 3 carbon atoms, and Y and Z may be the same or different or may form a single bond. Thus, the above purpose are achieved.
In a preferred embodiment of the present invention, the above compound is a spiro type and Y and Z form a single bond, and the compound is expressed by a general formula (II): 
In a preferred embodiment of the present invention, Ar1 and Ar2 are xcex2-naphthyl groups, each Ar1 and Ar2 is bound to xcex1-site of the other group, Xxe2x88x92 is a bromide anion, and the compound is expressed by a general formula (III): 
In a preferred embodiment of the present invention, both R1 and R2 are phenyl, or both R1 and R2 are xcex2-naphthyl.
Moreover, the present invention provides a method for producing the compound of the general formula (I), comprising reacting a compound of general formula (IV): 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different),
and R1 and R2 may be the same or different;
with a compound of general formula (V): 
and a compound of general formula (VI): 
wherein, in the general formulae (V) and (VI), Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom;
Ar1 and Ar2 may be the same or different;
X is a halogen atom; and
Y and Z are groups independently selected from the group consisting of a hydrogen atom; a halogen atom; an alkyl group having 1 to 4 carbon atoms; and an alkoxy group having 1 to 3 carbon atoms, and Y and Z may be the same or different or may form a single bond;
in this order or simultaneously, in the presence of an acid capturing agent and in an appropriate solvent.
Moreover, the present invention provides a method for producing the compound of the general formula (II), comprising reacting a compound of general formula (IV): 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different); and
R1 and R2 may be the same or different;
with a compound of general formula (VII): 
wherein
Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and Ar1 and Ar2 may be the same or different; X is a halogen atom;
in the presence of an acid capturing agent and in an appropriate solvent.
Moreover, the present invention provides a compound of general formula (VIII): 
wherein
R3 and R4 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and
R3 and R4 may be the same or different; and X is a halogen atom.
In a preferred embodiment of the present invention, both R3 and R4 are phenyl, or both R3 and R4 are xcex2-naphthyl, and X is a bromine atom.
Moreover, the present invention provides a method for producing a compound of general formula (III), comprising reacting optically active 3,5-dihydro-4H-dinaphtho[2,1-c:1xe2x80x2,2xe2x80x2-e]azepine expressed by a formula (IX): 
with a compound of a general formula (X): 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R1 and R2 may be the same or different; and;
X is a halogen atom;
in an alcoholic solvent and in a presence of inorganic base as an acid capturing agent.
Moreover, the present invention provides a method for producing the compound of claim 4, comprising reacting a compound of a formula (IX): 
with the compound of claim 8 in alcohol solvent and in the presence of inorganic base as an acid capturing agent.
Moreover, the present invention provides a compound of a general formula (XI): 
wherein
R3 and R4 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R3 and R4 may be the same or different.
In a preferred embodiment of the present invention, both R3 and R4 are phenyl, or both R3 and R4 are xcex2-naphthyl.
Further, the present invention provides a method for producing the compound of a general formula (VIII), comprising reacting the compound of claim 11 with an appropriate halogenating agent which can generate a halogen radical in an appropriate solvent and in the presence of appropriate radical reaction initiator to halogenate both 2- and 2xe2x80x2-methyl groups.
Moreover, the present invention provides a method for producing the compound of claim 8, comprising reacting the compound of claim 12 with brominating agent which can generate a bromine radical in an appropriate solvent and in the presence of appropriate radical reaction initiator to brominate both 2- and 2xe2x80x2-methyl groups.
Moreover, the present invention provides a compound of a general formula (XII): 
wherein
R3 and R4 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C3 alkyl) carbamoyl group; and a N,N-di(C1 to C3 alkyl) carbamoyl group (wherein alkyl may be the same or different), and
R3 and R4 may be the same or different; and
Tf is a trifluoromethanesulfonyl group.
In a preferred embodiment of the present invention, both R3 and R4 are phenyl, or both R3 and R4 are xcex2-naphthyl.
Moreover, the present invention provides a method for producing the compound of claim 11, comprising reacting the compound of claim 15 with methylmagnesium halide expressed by a general formula (XIII):
MeMgXxe2x80x83xe2x80x83(XIII)
wherein
X is a halogen atom,
in the presence of nickel catalyst in an appropriate solvent.
Moreover, the present invention provides a method for producing the compound of claim 12, comprising reacting the compound of claim 16 with methylmagnesium halide expressed by a general formula (XIII):
MeMgXxe2x80x83xe2x80x83(XIII)
wherein
X is a halogen atom,
in the presence of nickel catalyst in an appropriate solvent.
Moreover, the present invention provides a compound of a formula (XIV): 
wherein
Tf is a trifluoromethanesulfonyl group.
Moreover, the present invention provides a method for producing a compound of a general formula (XIIxe2x80x2): 
wherein
R3xe2x80x2 and R4xe2x80x2 are groups independently selected from the group consisting of an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C3 alkyl) carbamoyl group; and a N,N-di(C1 to C3 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R3xe2x80x2 and R4xe2x80x2 may be the same or different; and Tf is a trifluoromethanesulfonyl group, comprising:
substituting a bromine atom in the compound of claim 19 with R3xe2x80x2 and R4xe2x80x2 in an appropriate solvent and in the presence of transition metal catalyst.
Moreover, the present invention provides a method for producing the compound of a general formula (XVII): 
wherein
Ar3 and Ar4 are groups selected from the group consisting of an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and Ar3 and Ar4 may be the same or different; comprising
reacting the compound of claim 19 with a compound of a general formula (XV):
Ar3B(OH)2xe2x80x83xe2x80x83(XV)
and a compound of a general formula (XVI):
Ar4B(OH)2xe2x80x83xe2x80x83(XVI)
wherein, in the general formulae (XV) and (XVI), Ar3 and Ar4 are groups selected from the group consisting of an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a halogen atom, and Ar3 and Ar4 may be the same or different;
in this order or simultaneously, in an appropriate solvent and in the presence of base and palladium catalyst.
Moreover, the present invention provides a method for producing the compound of claim 16 comprising:
reacting the compound of claim 19 with a compound of a general formula (XV):
Ar3B(OH)2xe2x80x83xe2x80x83(XV)
and a compound of a general formula (XVI):
Ar4B(OH)2xe2x80x83xe2x80x83(XVI)
wherein, in the general formulae (XV) and (XVI), both Ar3 and Ar4 are phenyl or xcex2-naphthyl in an appropriate solvent and in the presence of base and palladium catalyst.
Moreover, the present invention provides a method for producing the compound of claim 19 comprising:
reacting the compound of a formula (XVIII): 
with a triflatating agent in an appropriate solvent and in the presence of base.
Further, the present invention provides a method for stereoselectively producing a compound of a general formula (XXI): 
wherein
R5 is alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an allyl or substituted allyl group having 3 to 9 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 3 carbon atoms or a halogen atom, or heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; or a propargyl or substituted propargyl group which has 3 to 9 carbon atoms which may be branched;
R6 and R7 are the same or different and may be a hydrogen atom, an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, with the proviso that they are not both hydrogen atoms;
R8 is a hydrogen atom; an aryl group which may be substituted with alkyl group having 1 to 3 carbon atoms, alkoxy group having 1 to 3 carbon atoms or a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and
R9 is an alkyl group having 1 to 4 carbon atoms; comprising;
alkylating a compound expressed by a general formula (XIX): 
wherein
R6 and R7 are the same or different and may be a hydrogen atom, an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, with the proviso that they are not both hydrogen atoms; R8 is a hydrogen atom; an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom;
and R9 is an alkyl group having 1 to 4 carbon atoms; with a compound of a general formula (XX):
R5xe2x80x94Wxe2x80x83xe2x80x83(XX)
wherein
R5 is an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an allyl or substituted allyl group having 3 to 9 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; or a propargyl or substituted propargyl group which has 3 to 9 carbon atoms which may be branched; and W is a functional group having leaving ability;
using the compound of claim 1, which is pure regarding axial chirality, as a phase-transfer catalyst in an appropriate solvent and in the presence of an inorganic base.
In a preferred embodiment of the present invention, the phase-transfer catalyst is the compound of claim 2.
In a preferred embodiment of the present invention, the phase-transfer catalyst is the compound of claim 3.
In a preferred embodiment of the present invention, the phase-transfer catalyst is the compound of claim 4.
The description and terms used herein are defined as follows:
The description xe2x80x9cwhich may be bunched or form a cyclic groupxe2x80x9d, used herein, means xe2x80x9cwhich may be a linear chain, branched chain or ring structurexe2x80x9d.
The term xe2x80x9calkyl group(s) having 1 to 6 carbon atoms which may be branched or form a cyclic groupxe2x80x9d means any of linear, branched or cyclic alkyl group(s) having 1 to 6 carbon atoms, including a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl and cyclohexyl group. In the present invention, a methyl, isopropyl or tert-butyl group is preferable.
The term xe2x80x9calkenyl group(s) having 2 to 6 carbon atoms which may be branched or form a cyclic groupxe2x80x9d means any of linear, branched or cyclic alkenyl group(s) having 2 to 6 carbon atoms, including an ethenyl, propenyl, isopropenyl, cyclopropenyl, butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, cyclobutenyl, penthenyl, cyclopenthenyl, hexthenyl and cyclohexthenyl group. In the present invention, a propenyl or a butenyl group is preferable.
The term xe2x80x9calkynyl group(s) having 2 to 6 carbon atoms and which may be branched or form a cyclic groupxe2x80x9d means any of linear, branched or cyclic alkynyl group(s) having 2 to 6 carbon atoms, including an ethynyl, propynyl, cycloproplethynyl, butynyl, 1-methyl-2-propynyl, pentynyl, cyclobutylethynyl, hexynyl, and trimethylsilylethynyl group. In the present invention, an ethynyl or trimethylsilylethynyl group is preferable.
The term xe2x80x9callyl or substituted allyl group(s) having 3 to 9 carbon atoms which may be branched or form a cyclic groupxe2x80x9d means allyl group(s), or any of substituted allyl group(s) having a substituent in 1 and/or 2 and/or 3 site and having total carbon atoms of 4 to 9, including a 2-butenyl, 1-cyclopentenylmethyl, and 3-methyl-2-butenyl group. In the present invention, an allyl group is preferarable.
The term xe2x80x9cpropargyl or substituted propargyl group(s) which having 3 to 9 carbon atoms which may be branchedxe2x80x9d means propargyl group, or any of substituted propargyl group(s) having substituent in 1 and/or 3 site and having 4 to 9 of total carbon atoms. The example includes 2-butynyl and 3-trimethylsilyl-2-propynyl. In the present invention, propargyl and 3-trimethylsilyl-2-propynyl are preferred.
The term xe2x80x9ca functional group having leaving abilityxe2x80x9d means an atom or an atomic group which is eliminated from a reaction substrate, in other words, a leaving group, in a substitution reaction or an elimination reaction. Examples of the group include a halogen atom and a sulfonyloxy group.
The xe2x80x9caralkyl groupxe2x80x9d used in the present invention includes a benzyl, phenethyl, naphthylmethyl and anthracenylmethyl group.
The xe2x80x9cheteroaralkyl groupxe2x80x9d used in the present invention includes a pyridylmethyl, quinonylmethyl, indolylmethyl, furylmethyl, thienylmethyl and pyrolylmethyl group.
The xe2x80x9caryl groupxe2x80x9d used in the present invention includes a phenyl, biphenyl, naphthyl and anthracenyl group.
The xe2x80x9cheteroaryl groupxe2x80x9d used in the present invention includes a pyridyl, quinolyl, pyrrolyl, imidazolyl, furyl, indolyl, thienyl, oxazolyl, and thiazolyl group.
The xe2x80x9chalogen atomxe2x80x9d used in the present invention includes a chlorine, bromine and iodine atom.
The xe2x80x9csulfonyloxy groupxe2x80x9d used in the present invention includes a methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethane sulfonyloxy group.
An appropriate solvent includes benzene, toluene, xylene, ethylether, isopropylether, tetrahydrofuran, dioxane, or the like. Among them, two phase system comprising water immissible solvent and water. The inorganic base includes lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, rubidium hydroxide, cesium hydroxide or the like.
The inventor has found that optically active quarternary ammonium salts expressed by the general formula (I) that can form a spiro structure and an axial chirality, functions as an excellent phase-transfer catalyst in the two-phase medium including organic solvent and water: 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R1 and R2 may be the same or different; Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and Ar1 and Ar2 may be the same or different; Xxe2x88x92 is a halide anion; and Y and Z are groups independently selected from the group consisting of a hydrogen atom; a halogen atom; an alkyl group having 1 to 4 carbon atoms; and an alkoxy group having 1 to 3 carbon atoms, and Y and Z may be the same or different or may form a single bond.
The inventor has found that, by using the optically active quarternary ammonium salt expressed by the general formula (I), an optically active xcex1-amino acid derivative expressed by the general formula (XXI) having high optical purity is produced: 
wherein
R5 is an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an allyl or substituted allyl group having 3 to 9 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; or a propargyl or substituted propargyl group which has 3 to 9 carbon atoms that may be branched;
R6 and R7 are the same or different and are hydrogen atoms, an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, with the proviso that they are not both hydrogen atoms;
R8 is a hydrogen atom; an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and R9 is an alkyl group having 1 to 4 carbon atoms; and * is a newly produced chiral center;
by stereoselectively alkylating a glycine derivative expressed by the general formula (XIX): 
wherein
R6 and R7 are the same or different and are hydrogen atoms, an aryl group which may be substituted with alkyl group having 1 to 3 carbon atoms, alkoxy group having 1 to 3 carbon atoms or a halogen atom, with proviso that they are not both hydrogen atoms; R8 is a hydrogen atom; an aryl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group;an aralkyl group which may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and R9 is an alkyl group having 1 to 4 carbon atoms;
with a compound expressed by the general formula (XX):
R5xe2x80x94Wxe2x80x83xe2x80x83(XX)
wherein
R5 is an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an allyl or substituted allyl group having 3 to 9 carbon atoms which may be branched or form a cyclic group; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, or a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; or a propargyl or substituted propargyl group which has 3 to 9 carbon atoms that may be branched; and W is a functional group having an ability to eliminate sulfonyloxy group and the like.
In the optically active quarternary ammonium salt with the axial chirality expressed by the general formula (I), when the spiro type quarternary ammonium salts with the axial chirality expressed by the general formula (II) are employed as phase-transfer catalyst, a higher stereoselective alkylation can be performed: 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and
R1 and R2 may be the same or different;
Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and
Ar1 and Ar2 may be the same or different;
Xxe2x88x92 is a halide anion.
Particularly, in the compound of general formula (II), optically active spiro type quarternary ammonium salt (in which Ar1 and Ar2 are xcex2-naphthyl groups, each Ar1 and Ar2 is bound to xcex1-site of the other group, and Xxe2x88x92 is a bromide anion) having C2-symmetric axial chirality expressed by the general formula (III): 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different); R1 and R2 may be the same or different; and, in particular, both R1 and R2 are phenyl, or both R1 and R2 are xcex2-naphthyl;
are used as particularly useful phase-transfer catalyst, thereby providing the above-mentioned stereoselective alklation of 90% e.e. or more.
The optically active quarternary ammonium salt, with an axial chirality and which may form a spiro structure, expressed by the general formula (I) can be produced by reacting an optically active dinaphthoazepine derivative with an axial chirality, expressed by the general formula (IV): 
wherein
R1 and R 2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R1 and R2 may be the same or different;
with a compound of general formula (V): 
and a compound of general formula (VI): 
wherein, in the general formulae (V) and (VI), Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group (such as phenyl, biphenyl, naphthyl) which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group (such as pyridyl, quinonyl) which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and Ar1 and Ar2 may be the same or different;
X is a halogen atom; and
Y and Z are groups independently selected from the group consisting of a hydrogen atom; a halogen atom; an alkyl group having 1 to 4 carbon atoms; and an alkoxy group having 1 to 3 carbon atoms, and
Y and Z may be the same or different or may form a single bond;
in this order or simultaneously, in the presence of an acid capturing agent and in an appropriate solvent.
The compound of general formula (IV) can be produced by subjecting the compound of general formula (VIII) to a method of Hawkins, J. M. et al. (Hawkins, J. M. et al., J. Org. Chem., 1994, 59, 649). A number of the compounds expressed by the general formulae (V) and (VI) are commercially available as a reagent. Alternatively, the compound of general formula (VIII) may be used in place of these compounds.
According to the present invention, a compound of general formula (I) can be produced by stirring a compound of general formula (IV) and (V) and (VI) in an alcoholic solvent in the presence of an acid capturing agent at an appropriate temperature. Compound (V) and (VI) can be used preferably 0.8 to 1.5 equivalents, more preferably 1.0 to 1.4 equivalents and most preferably 1.1 to 1.2 equivalents to the compound of the general formula (IV), respectively. The example of the alcohol includes methanol, ethanol, propanol, isopropylalcohol, butanol and tert-butylalcohol. Example of the acid capturing agent includes potassium carbonate and sodium carbonate. The temperature can be between room temperature and a boiling temperature of the solvent used, preferably between room temperature and 80xc2x0 C. The stirring period can bepreferably 30 minutes to 12 hours, more preferably 2 to 11 hours and most preferably 3 to 10 hours. In the reaction, above-mentioned solvent may be used preferably 5 to 50 times, more preferably 10 to 40 times of volume (mL) based on the weight (g) of compound of general formula (IV). The acid capturing agent may be used preferably 2 to 4 equivalents and more preferably 2 to 3 equivalents to the compound of general formula (IV).
The optically active spiro type quarternary ammonium salt with an axial chirality and expressed by the general formula (II) can be produced by reacting a compound of general formula (IV) with a compound of general formula (VII): 
wherein
Ar1 and Ar2 are groups independently selected from the group consisting of an aryl group such as phenyl, biphenyl, naphthyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group such as a pyridyl group or quinonyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom;
Ar1 and Ar2 may be the same or different; and
X is a halogen atom;
in the presence of an acid capturing agent in an appropriate solvent.
According to the present invention, a compound of general formula (II) can be produced by stirring a compound of general formula (IV) and (VII) in an alcohol solvent in the presence of an acid capturing agent at an appropriate temperature. The compound of general formula (VII) can be used preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents and most preferably 1 to 1.5 equivalents to the compound of general formula (IV). Example of the alcohol includes methanol, ethanol, propanol, isopropylalcohol, butanol and tert-butylalcohol. Example of the acid capturing agent includes potassium carbonate and sodium carbonate. The temperature can be between room temperature and a boiling point of the solvent used, preferably between room temperature and 80xc2x0 C. The stirring period can bepreferably 30 minutes to 12 hours, more preferably 1 to 11 hours and most preferably 2 to 10 hours.
In the reaction, above-mentioned solvent may be used preferably 5 to 50 times, more preferably 5 to 30 times and most preferably 10 to 25 times of volume (mL) based on the weight of the compound of general formula (IV). The acid capturing agent may be used at the weight of preferably 2 to 4 equivalents and more preferably 2 to 3 equivalents to the compound of general formula (IV).
The optically active spiro type quarternary ammonium salt with an axial chirality and expressed by the general formula (III) can be produced by reacting optically active 3,5-dihydro-4H-dinaphtho[2,1-c:1xe2x80x2,2xe2x80x2-e]azepine expressed by the general formula (IX) with optically active 1,1xe2x80x2-binaphthyl derivative expressed by the general formula (X): 
wherein
R1 and R2 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R1 and R2 may be the same or different; and; X is a halogen atom;
in alcoholic solvent in the presence of inorganic base as an acid capturing agent.
The optically active 3,5-dihydro-4H-dinaphtho[2,1-c:1xe2x80x2,2xe2x80x2-e]azepine (IX) can be produced by the method by Hawkins et al (Hawkins, J. M. et al., J. Org. Chem. 1994, 59, 649).
According to the present invention, a compound of general formula (III) can be produced by stirring a compound of general formula (IX) with a compound of general formula (X) in an alcoholic solvent in the presence of an acid capturing agent at an appropriate temperature.
The compound of general formula (X) can be used preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents and most preferably 1 to 1.5 equivalents to the compound of general formula (IX). Example of the alcohol includes methanol, ethanol, propanol, isopropylalcohol, butanol and tert-butylalcohol. Example of the acid capturing agent includes potassium carbonate and sodium carbonate. The temperature can be between room temperature and a boiling point of the solvent used, preferably between room temperature and 80xc2x0 C.
The stirring period can be preferably 30 minutes to 12 hours, more preferably 1 to 11 hours and most preferably 2 to 10 hours. In the reaction, above-mentioned solvent may be used preferably 5 to 50 times, and more preferably 5 to 30 times of volume (mL) based on the weight (g) of the compound of general formula (IX). The acid capturing agent may be used at the weight of preferably 2 to 4 equivalents and more preferably 2 to 3 equivalents to the compound of general formula (IX).
The compound expressed by the general formula (X) can be produced by reacting the optically active 2,2xe2x80x2-dimethyl-1,1xe2x80x2-binaphthyl derivative expressed by the general formula (XI): 
wherein
R3 and R4 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C4 alkyl) carbamoyl group; and a N,N-di(C1 to C4 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R3 and R4 may be the same or different;
with an appropriate halogenating agent (halogen radical generating agent) which can generate a halogen radical in an appropriate solvent and in the presence of appropriate radical reaction initiator to halogenate both 2- and 2xe2x80x2-methyl groups.
According to the present invention, a compound of general formula (X) can be produced by stirring a compound of general formula (XI) with a radical reaction generating agent in the presence of radical reaction initiator in a hydrocarbon solvent at an appropriate temperature.
The compound of the general formula (XI) can be used preferably 2 to 3 equivalents and more preferably 2 to 2.5 equivalents to the halogen radical reaction generating agent. Example of the radical reaction generating agent includes a N-bromosuccinimide. Example of the halogen radical reaction initiator includes benzoyl peroxide. Example of the hydrocarbon solvent includes hexane, cyclohexane and petroleum ether. The stirring temperature is between room temperature and a boiling point of the solvent used, preferably between 60xc2x0 C. and 100xc2x0 C. The stirring period can bepreferably 30 minutes to 5 hours, more preferably 1 to 5 hours and most preferably 1 to 3.5 hours. In the reaction, the solvent may be used preferably 5 to 20 times, more preferably 5 to 15 times and most preferably 5 to 10 times of volume (mL) based on weight of the compound of general formula (XI). The radical reactin initiator may be used preferably 0.1 to 0.6 equivalents and more preferably 0.2 to 0.6 equivalents to the compound of general formula (XI). The halogen radical reaction initiator may be used preferably 1 to 5 equivalents, more preferably 1.5 to 3.5 equivalents and most preferably 1.8 to 2.6 equivalents to the compound of general formula (XI).
A compound expressed by the general formula (XI) can be produced by reacting the optically active 2,2xe2x80x2-bistrifluoromethanesulfonyloxy-1,1xe2x80x2-binaphthyl derivative expressed by the general formula (XII): 
wherein
R3 and R4 are groups independently selected from the group consisting of a hydrogen atom; an alkyl group having 1 to 6 carbon atoms which may be branched or form a cyclic group; an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an alkynyl group having 2 to 6 carbon atoms which may contain branched or cyclic structure; an aralkyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; a (C1 to C3 alkoxy) carbonyl group; a carbamoyl group; a Nxe2x80x94(C1 to C3 alkyl) carbamoyl group; and a N,N-di(C1 to C3 alkyl) carbamoyl group (wherein alkyl may be the same or different), and R3 and R4 may be the same or different; and Tf is a trifluoromethanesulfonyl group;
with methylmagnesium halide expressed by the general formula (XIII):
MeMgXxe2x80x83xe2x80x83(XIII)
wherein
X is a halogen atom;
in the presence of a nickel catalyst and in an appropriate solvent.
According to the present invention, a compound of general formula (XI) can be produced by stirring a compound of general formula (XII) with compound (XIII) in the presence of a nickel catalyst in an ether solvent at an appropriate temperature.
The compound (XIII) can be used preferably 2 to 7 equivalents and more preferably 2.5 to 6.5 equivalents to the compound of general formula (XII). Example of the compound (XIII) includes MeMgCl. Example of the nickel catalyst includes NiCl2(PPh3)2. Example of the ether solvent includes ether, isopropylether, butylether, THF and tert-butylmethylether. The temperature can be between xe2x88x9215xc2x0 C. and a boiling point of the solvent used, preferably between 0xc2x0 C. and 50xc2x0 C. The stirring period can be preferably 2 to 50 hours and more preferably 5 to 40 hours. In the reaction, solvent may be used preferably 5 to 20 times, more preferably 7 to 15 times of volume (mL) based on the weight of the compound of the general formula (XII). The nickel catalyst may be used at the weight of preferably 0.01 to 0.1 equivalents and more preferably 0.02 to 0.06 equivalents to the compound of general formula (XII).
When R3 and R4 are functional groups other than hydrogen atom, the compound (XII) can be produced by applying a method catalyzed by palladium such as carbonylation reaction, Heck reaction, Stille reaction, Sonogashira reaction or Suzuki reaction to an optically active 3,3xe2x80x2-dibromo-2,2xe2x80x2-bistrifluoromethane-sulfonyloxy-1,1xe2x80x2-binaphthyl derivative expressed by formula (XIV): 
wherein
Tf is a trifluoromethanesulfonyl group;
Particularly, the compound expressed by the general formula (XVII): 
wherein
Ar3 and Ar4 are groups selected from the group consisting of an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom; and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, and Ar3 and Ar4 may be the same or different;
can be produced by reacting the compound (XIV) with a compound of general formula (XV):
Ar3B(OH)2xe2x80x83xe2x80x83(XV)
and a compound of general formula (XVI):
Ar4B(OH)2xe2x80x83xe2x80x83(XVI)
wherein, in the general formulae (XV) and (XVI), Ar3 and Ar4 are groups selected from the group consisting of an alkenyl group having 2 to 6 carbon atoms which may be branched or form a cyclic group; an aryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a halogen atom;
and a heteroaryl group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a halogen atom, and Ar3 and Ar4 may be the same or different;
in this order or simultaneously, in an appropriate solvent and in the presence of base and palladium catalyst.
According to the present invention, the compound of the general formula (XVII) can be produced by stirring a compound of the general formula (XIV) with a compound of the general formula (XV) and a compound of the general formula (XVI) in an ether solvent or DMF in the presence of a palladium catalyst and a base at an appropriate temperature.
The compounds of the general formulae (XV) and (XVI) can be used preferably 1.2 to 3 equivalents, more preferably 1.2 to 2.0 equivalents and most preferably 1.25 to 1.75 equivalents to the compound of the general formula (XIV), respectively. Example of the ether solvent includes ether, isopropylether, butylether, THF and tert-butylmethylether. Example of the base includes sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, thallium hydroxide, sodium methoxide, sodium ethoxide and potassium phosphate (hydrate). The palladium catalyst can be added preferably 0.01 to 0.1 equivalents, more preferably 0.02 to 0.08 equivalents and most preferably 0.03 to 0.06 equivalents to the compound (XIV). The temperature can be between room temperature and a boiling point of the solvent used, preferably between room temperature and 100xc2x0 C. The stirring can be preferably 1 to 20 hours, more preferably 3 to 15 hours and most preferably 6 to 12 hours. In the reaction, solvent may be used preferably 5 to 20 times and more preferably 6 to 12 times of volume (mL) based on the weight of the compound of general formula (XIV). The base may be used preferably 2 to 5 equivalents and more preferably 2.5 to 3.5 equivalents to the compound of general formula (XIV). Example of the palladium catalyst includes 0 equivalent of palladium complex such as Pd(PPh3)4 and a catalyst generated in the reaction solvent by Pd(OAc)2 and PPh3. In the latter example, the ratio of Pd(OAc)2 to PPh3 can be from 1:4 to 1:5.
A compound (XIV) can be produced by reacting an optically active 2,2xe2x80x2-dibromo-1,1xe2x80x2-bi-2-naphthol expressed by formula (XVIII): 
with a triflatating agent in an inert solvent in the presence of base at a temperature from xe2x88x9278xc2x0 C. to 0xc2x0 C. Example of the inert solvent includes toluene, methylene chloride, THF and DMF. The base can be used preferably 2 to 4 equivalents, more preferably 2.5 to 3.3 equivalents to the compound (XVIII). Example of the triflatating agent includes trifluoromethanesulfonic anhydride and trifluoromethanesulfinyl chloride. The triflatating agent can be used preferably 2 to 2.5 equivalents, more preferably 2.2 to 2.5 equivalents to the compound (XVIII). In this reaction, the reaction solvent may be used preferably 5 to 20 times and more preferably 6 to 15 times of volume (mL) based on the weight of the compound of general formula (XV). Example of the base includes tertiary amine such as triethylamine, N,N-dimethylisopropylamine and N-methylmorpholine.
The optically active quarternary ammonium salts (I) to (III) produced by the above methods having axial chirality and able to form spiro type structure are useful as a phase-transfer catalyst for stereoselective alkylation of the compound (IX).
The compound of general formula (I) is pure regarding axial chirality, and used as a phase-transfer catalyst. The term xe2x80x9cpure regarding axial chiralityxe2x80x9d means that the percentage of one of the isomer is larger than the percentage of other isomers in a variety of isomers based on the axial chirality. The percentage of the one of the isomer is 90% or more, preferably 95% or more, and even more preferably 98% or more.
According to the present invention, an optically active compound (XXI) can be produced by stirring a compound (XIX) with any one of compounds (I) to (III) that can act as a phase-transfer catalyst in two-phase mixture comprising a hydrocarbon solvent and an alkaline aqueous solution at an appropriate temperature. The compound (XX) can be added preferably 1 to 1.5 equivalents, more preferably 1.1 to 1.3 equivalents and most preferably 1.2 to 1.25 equivalents to the compound (XIX). The compound (I) to (III) can be added preferably 0.005 to 0.03 equivalents and more preferably 0.0075 to 0.0125 equivalents to the compound (XIX). The temperature can be between xe2x88x9210xc2x0 C. and room temperature, preferably between xe2x88x925xc2x0 C. and +5xc2x0 C. The stirring period can be preferably 15 minutes to 3 hours, more preferably 0.5 to 2 hours and most preferably 0.5 to 1.5 hours. Using above-mentioned methods, optically active compound (XXI) can be produced with high yield and high optical purity.
The hydrocarbon solvent used in the present invention includes any type of solvent which is immiscible to water, and includes hexane, toluene or the like. The solvent may be used preferably 5 to 30 times and more preferably 8 to 25 times of volume (mL) based on the weight of the compound of general formula (XIX). The alkaline aqueous solution may be used as 10 to 60% aqueous solution of alkaline metal hydroxide such as lithium hydroxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, rubidium hydroxide or the like. The alkaline aqueous solution may be used at the ratio of volume (mL) to weight (g) of preferably 4 to 20 times and more preferably 8 to 15 times based on the compound of general formula (XIX).
For example, for the synthesis of (S)-form of the compound (XXI), compound (I) with an axial chirality of (S) can be used. On the other hand, for the synthesis of (R) form, compound (I) with an axial chirality of (R) can be used.
The term xe2x80x9chigh optical purityxe2x80x9d used herein means optical purity of preferably 90% e.e. or more and more preferably 95% e.e.